PROJECT ABSTRACT Major depressive disorder (MDD) is ranked second among all diseases in global impact. Unfortunately, many patients have treatment-resistant MDD (TRD), for which the most effective antidepressant treatment option is electroconvulsive therapy (ECT). However, the neurocognitive adverse effects (e.g., anterograde and retrograde amnesia) induced by ECT mitigate the attainment of desired clinical outcomes. As such, the development of new and safe neuromodulatory antidepressant interventions is strongly warranted. One new type of neuromodulation treatment that has antidepressant properties and is under active development is magnetic seizure therapy (MST). MST is neurocognitively safer than ECT because it uses magnetic rather than electrical fields to induce seizures, which have shallower penetration and therefore avoid the undesired side- effect of delivering intense electrical stimulation to the medial temporal lobe. As yet there has been no research into the neuromechanisms underlying MST?s antidepressant and neurocognitive effects. To systematically uncover these mechanisms, we are building upon an international, NIMH funded (R01 MH112815), US Food and Drug Administration Investigational Device Exemption (IDE; #G170127) approved clinical study that will compare and contrast clinical and neurocognitive outcomes of ECT and MST. The goal of this R01 is to conduct research Ascertaining Neurocircuitry to Enhance Neuromodulation Development (ASCEND). In the proposed study, we will capitalize on that project by adding advanced magnetic resonance imaging (MRI), individualized 3-D computational head modeling of ECT and MST (E-fields in stimulated brain regions), and neurophysiological modeling of activity propagation and plasticity resulting from each treatment type. This innovative 5-year project has two aims: 1) Determine the common and distinct neural circuit correlates of antidepressant treatment response between RUL-UB-ECT and MST, and 2) Determine the common and distinct neural circuit correlates of memory side effects between RUL-UB-ECT and MST. The proposed study will draw upon an interdisciplinary team from diverse backgrounds including translational neurocognitive science, neuropsychology, computational neuroscience, psychiatry, neuroimaging, bioengineering, and biostatistics. The synthesis of physical (E-field) and physiological (neural activity and dynamics) computational modeling and MRI with the clinical and neurocognitive metrics from the current NIMH-funded clinical trial will allow us to determine neuromodulation-induced changes in neurocircuitry, and their corresponding relationships to behavior. Such knowledge will elucidate the neural mechanisms of antidepressant seizure therapy (ECT, MST) to inform new treatment methods that optimally target neurocircuitry related to symptom improvement, while ensuring neurocognitive safety. These developments will make a major contribution to improving the lives of the many patients with TRD and yield a substantial positive public health impact.